ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.799A>G (p.Thr267Ala) (rs876660962)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000214811 SCV000278809 uncertain significance not provided 2017-07-26 criteria provided, single submitter clinical testing This variant is denoted ATM c.799A>G at the cDNA level, p.Thr267Ala (T267A) at the protein level, and results in the change of a Threonine to an Alanine (ACT>GCT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. ATM Thr267Ala was not observed in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Threonine and Alanine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. ATM Thr267Ala occurs at a position that is not conserved and is not located in a known functional domain. In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether ATM Thr267Ala is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000567197 SCV000660713 uncertain significance Hereditary cancer-predisposing syndrome 2018-03-29 criteria provided, single submitter clinical testing Insufficient evidence
Invitae RCV000818514 SCV000959132 uncertain significance Ataxia-telangiectasia syndrome 2019-10-11 criteria provided, single submitter clinical testing This sequence change replaces threonine with alanine at codon 267 of the ATM protein (p.Thr267Ala). The threonine residue is moderately conserved and there is a small physicochemical difference between threonine and alanine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with ATM-related disease. ClinVar contains an entry for this variant (Variation ID: 234262). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The alanine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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